Leydig cell hyperplasia and adenoma formation: Mechanisms and relevance to humans
Leydig cell hyperplasia and adenoma formation: Mechanisms and relevance to humans
复制标题
DOI：
10.1016/s0890-6238(96)00203-1
复制
发表时间：
1997-01-01
影响因子：
3.3
通讯作者：
Foster, GP
中科院分区：
文献类型：
--
作者：
Clegg, ED;Cook, JC;Foster, GP
间质细胞腺瘤在评估化学制剂对实验动物的慢性毒性的研究中经常被观察到，人们对这种反应与人类风险评估的相关性提出了怀疑，但这种相关性的问题还没有被广泛的专家小组以全面的方式评估和提出，本文报告了一个关于啮齿动物间质细胞腺瘤与人类相关性的研讨会的一致结论。讨论了间质细胞生物学和毒理学的五个方面：1)间质细胞增殖的控制；2)毒物诱导间质细胞增殖和肿瘤发生的机制；3)间质细胞腺瘤的病理学；4)间质细胞腺瘤的流行病学；5)间质细胞肿瘤发生的风险评估。还确定了重要的研究需求，存在关于男性间质细胞腺瘤真实发病率的不确定性，尽管明显的发病率很少并且主要限于白人男性，而且，在测试物种中引起LeyDigi细胞增生或腺瘤的特定治疗剂以及尼古丁和乳糖的监测数据库没有发现在人类中的发病率增加，因为存在关于人类真实发病率的不确定性，在某些情况下，在测试物种中诱导Leydig细胞腺瘤可能是令人担忧的，在终生暴露于化学品之后，在测试物种中单独发生间质细胞增生不构成致癌潜力风险评估中令人担忧的原因，但早期发生可能表明需要进行额外的测试，睾丸间质细胞腺瘤在试验物种中的出现是一个潜在的令人担忧的问题，因为如果诱导方式和潜在暴露不能被排除为与人类相关，工作组集中在七种荷尔蒙诱导模式上，其中两种，促性腺激素释放激素激动剂和多巴胺激动剂，被认为与人类无关，雄激素受体拮抗剂，5α-还原酶抑制，睾酮生物合成抑制，芳香化酶抑制，和雌激素激动剂被认为是相关的或潜在的相关的，但不同物种之间可能存在数量上的差异，啮齿动物更敏感，暴露的边缘(MOE；对于通过与人类相关的荷尔蒙模式导致间质细胞腺瘤的化合物，应使用与毒性相关的最低暴露水平与人类暴露水平的比率)。对于突变阳性的试剂，关于MOE或线性外推方法的决定应该在个案的基础上做出，在缺乏关于诱导模式的信息的情况下，有必要利用默认假设，包括低于可观察范围的线性行为，所有证据都应该在决策过程中权衡。(C)1997年爱思唯尔科学公司。
Leydig cell adenomas are observed frequently in studies evaluating the chronic toxicity of chemical agents in laboratory animals, Doubts have been raised about the relevance of such responses for human risk assessment, but the question of relevance has not been evaluated and presented in a comprehensive manner by a broad group of experts, This article reports the consensus conclusions from a workshop on rodent Leydig cell adenomas and human relevance. Five aspects of Leydig cell biology and toxicology were discussed: 1) control of Leydig cell proliferation; 2) mechanisms of toxicant-induced Leydig cell hyperplasia and tumorigenesis; 3) pathology of Leydig cell adenomas; 4) epidemiology of Leydig cell adenomas; and 5) risk assessment for Leydig cell tumorigens. Important research needs also were identified, Uncertainty exists about the true incidence of Leydig cell adenomas in men, although apparent incidence is rare and restricted primarily to white males, Also, surveillance databases for specific therapeutic agents as well as nicotine and lactose that have induced Leydig cell hyperplasia or adenoma in test species have detected no increased incidence in humans, Because uncertainties exist about the true incidence in humans, induction of Leydig cell adenomas in test species may be of concern under some conditions, Occurrence of Leydig cell hyperplasia alone in test species after lifetime exposure to a chemical does not constitute a cause for concern in a risk assessment for carcinogenic potential, but early occurrence may indicate a need for additional testing, Occurrence of Leydig cell adenomas in test species is of potential concern as both a carcinogenic and reproductive effect if the mode of induction and potential exposures cannot be ruled out as relevant for humans, The workgroup focused on seven hormonal modes of induction of which two, GnRH agonism and dopamine agonism, were considered not relevant to humans, Androgen receptor antagonism, 5 alpha-reductase inhibition, testosterone biosynthesis inhibition, aromatase inhibition, and estrogen agonism were considered to he relevant or potentially relevant, but quantitative differences may exist across species, with rodents being more sensitive, A margin of exposure (MOE; the ratio of the lowest exposure associated with toxicity to the human exposure level) approach should be used for compounds causing Leydig cell adenoma by a hormonal mode that is relevant to humans. For agents that are positive for mutagenicity, the decision regarding a MOE or linear extrapolation approach should be made on a case-by-case basis, In the absence of information about mode of induction, it is necessary to utilize default assumptions, including linear behavior below the observable range, All of the evidence should be weighed in the decision-making process. (C) 1997 Elsevier Science Inc.